The present invention relates generally to cancer and, more specifically, to human monoclonal antibodies for the treatment and diagnosis of cancer.
Cancer is one of the leading causes of death in the United States. Each year, more than half a million Americans die from cancer, and more than one million are newly diagnosed with the disease. In cancer, neoplastic cells escape from their normal growth regulatory mechanisms and proliferate in an uncontrolled fashion, leading to the development of a malignant tumor. Tumor cells can metastasize to secondary sites if treatment of the primary tumor is either not complete or not initiated before substantial progression of the disease. Early diagnosis and effective treatment of malignant tumors is therefore essential for survival.
The current methods for treating cancer include surgery, radiation therapy and chemotherapy. A major problem with each of these treatments is their lack of specificity for cancer cells. For instance, surgical removal of the tumor is often incomplete. Even a few residual neoplastic cells can be lethal, as they can rapidly proliferate and metastasize to other sites. Radiation and chemotherapy also have serious limitations. These therapies target all growing cells of the body, including both normal and neoplastic cells. Due to their toxicity to normal tissues, the amount of radiation or chemotherapeutic agent that can be safely used is often inadequate to kill all neoplastic cells. Additionally, their toxicity to normal tissues is manifested by unpleasant side effects, including nausea and hair loss, that severely reduce the quality of life for the cancer patient undergoing these treatments. Clearly, a more selective and effective means of treating cancer is needed.
Monoclonal antibodies are homogeneous preparations of immunoglobulin proteins that specifically recognize and bind to regions, or epitopes, of their corresponding antigens. Neoplastic cells selectively express antigens which are not present on normal cells. Thus, monoclonal antibodies can be produced that are directed against tumor-specific antigens. Such tumor-specific antigens can be linked to therapeutic moieties that kill or arrest the growth of neoplastic cells. In addition, monoclonal antibodies can be linked to diagnostic moieties that allow the imaging of neoplastic cells. Thus, monoclonal antibodies directed against antigens selectively expressed by tumor cells compared to normal cells can be beneficially used for the early detection and effective treatment of cancer.
Most current immunotherapeutic strategies for cancer have been of limited utility due to their reliance on mouse monoclonal antibodies. Mouse monoclonal antibodies can be produced easily and in virtually unlimited quantities using hybridoma technology. However, when administered to humans, they can be recognized as foreign by the human immune system and be neutralized before exerting their therapeutic effect on the diseased tissue. Furthermore, the murine immune system often preferentially recognizes immunodominant epitopes of normal human antigens present on tumor cells. Thus, human tumor-specific antigens often fail to generate therapeutically beneficial murine antibodies.
Human monoclonal antibodies can overcome both of these limitations. Most importantly, human monoclonal antibodies are not as immunogenic as murine antibodies. Therefore, tumor-specific human monoclonal antibodies will be able to more effectively target and eliminate neoplastic cells. Furthermore, the human immune system is less likely to generate antigens against epitopes present on normal cells, increasing the odds of generating and successfully identifying tumor-specific antigens. Additionally, the repertoire of the human immune system is different from that of the mouse, containing potentially novel antibody specificities.
Current procedures to produce tumor-specific human monoclonal antibodies have generally started with lymphocytes obtained from tumor-bearing patients. These procedures rely on the stimulation and expansion of tumor-reactive lymphoctyes in vivo. These procedures are seriously limited by the narrow range of antigen specificities of activated B-cells of cancer patients. As it is clearly not possible to immunize individuals in vivo with tumor cells, as one can with mice, it has not been possible to readily generate tumor-specific human monoclonal antibodies to any given antigen or tumor cell type. Procedures for generating tumor-specific antibodies of any desired specificity would be very beneficial for effective immunotherapy and immunodiagnosis.
Thus, there exists a need for improved tumor-specific human monoclonal antibodies for the therapy and diagnosis of cancer. The present invention satisfies this need and provides related advantages as well.
The invention provides a human monoclonal antibody or functional fragments thereof, having at least one Complementarity Determining Region (CDR) with substantially the amino acid sequence of a CDR of SEQ ID NO:2 or SEQ ID NO:4. Also provided is a human monoclonal antibody or functional fragment thereof, with at least one CDR having substantially the amino acid sequence of a CDR of SEQ ID NO:6 or SEQ ID NO:8. The invention also provides human monoclonal antibodies or functional fragments produced by the cell lines H1140, H2420 or H935. H1140, H2420 and H935 hybridoma cell lines are also provided.
The invention further provides a nucleic acid encoding a human monoclonal antibody or functional fragment thereof, having a nucleotide sequence encoding substantially the amino acid sequence of at least one CDR encoded by SEQ ID NO:1 or SEQ ID NO:3. Also provided is a nucleic acid encoding a human monoclonal antibody or functional fragment thereof, having a nucleotide sequence encoding substantially the amino acid sequence of at least one CDR encoded by SEQ ID NO:5 or SEQ ID NO:7.
A method for reducing neoplastic cell proliferation is also provided. The method consists of administering an effective amount of a human monoclonal antibody or functional fragment of the invention. Also provided is a method of detecting a neoplastic cell in a sample. The method consists of contacting a cell with a monoclonal antibody or functional fragment of the invention and detecting the specific binding of the human monoclonal antibody or functional fragment to the sample. The presence or increased level compared to a normal cell of the monoclonal antibody or functional fragment indicates the presence of a neoplastic cell in the sample.